The causes of bipolar disorder (BD) are unknown, but neuroimaging studies have identified abnormalities in fronto-limbic brain (FLB) regions, which parallel findings of neurocognitive impairment. There is growing evidence to support abnormalities in sub- regions of the prefrontal cortex (PFC) and medial temporal lobe. In particular, the most consistent findings implicate the dorsolateral PFC, anterior cingulate, amygdala and hippocampus. These brain regions are interlinked and abnormalities could result in emotional instability, behavioral activation and other symptoms seen in BD patients. The primary aim of our study is to determine the extent to which FLB pathology in BD is attributable to genetic effects. The relationship between FLB abnormalities and BD will be addressed in a control study of same-gender sibling pairs discordant for BD type I. We will enroll 60 male and female sibling pairs discordant for BD and 60 matched controls, in a 3 group design (BD probands, unaffected siblings and healthy controls). Each subject will undergo brain magnetic resonance imaging (MRI), spectroscopy (MRS), diffusion tensor imaging (DTI) scans and neurocognitive testing. We will examine the relationship between BD and FLB abnormalities, neurocognitive function and genetic vulnerability. We will use state-of-the art tools from brain imaging and cognitive neuroscience to study the contribution of familial factors in determining FLB impairment in sibling pairs discordant for BD. The study will further elucidate the pathophysiology of BD and the role of genetic factors in the genesis of such abnormalities. If our hypotheses are confirmed, this will indicate that FLB abnormalities in BD are heritable and could be viable endophenotypes in the search for the specific genes involved. PUBLIC HEALTH RELEVANCE: Bipolar disorder is a very prevalent psychiatric illness and a major health problem worldwide. This study will examine the role of heritability on key brain abnormalities involved in causation of bipolar disorder (BD). If our hypotheses are confirmed, this will indicate that abnormalities in fronto-limbic brain regions in patients with BD are heritable and could be utilized as endophenotypes to guide future research on the specific genes involved.